Novel Role for -Catenin in the Regulation of Cancer Cell Migration via the Induction of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1)

Background: -Catenin is a tumor suppressor in lung cancer. Results: -Catenin is a novel regulator of HAI-1 and cell migration. Conclusion: -Catenin and HAI-1 regulate cell migration and sensitize NSCLC cells to c-MET inhibitor. Significance: Targeting -catenin-mediated HAI-1 expression might be a new strategy to treat lung cancer. -catenin (Plakoglobin), a well-described structural protein functioning at the adherens junctions and desmosomes, was shown to be either lost or weakly expressed in non-small cell lung cancer (NSCLC) cells and tumor tissues. However, the tumor suppressive affects of -catenin were not fully understood. In this study, we have identified a novel role for the affects of -catenin on non-small cell lung cancer (NSCLC) cell migration. Expression of -catenin in NSCLC cells resulted in reduced cell migration as determined by both scratch assays and trans-well cell migration assays. Moreover, the affects of -catenin on cell migration were observed to be p53-dependent. Mechanistically, the anti-migratory effects seen via -catenin were driven by the expression of hepatocyte growth factor activator inhibitor Type I (HAI-1 or SPINT-1), an upstream inhibitor of the c-MET signaling pathway. Furthermore, the re-expression of -catenin sensitized NSCLC cells to c-MET inhibitor-mediated growth inhibition. Taken together, we identify -catenin as a novel regulator of HAI-1, which is a critical regulator of HGF/c-MET signaling. Therefore, targeting -catenin-mediated HAI-1 expression might be a useful strategy to sensitize NSCLC to c-MET inhibitors.